Pulmonary fibroblast activation during Aspergillus fumigatus infection enhances lung defense via immunomodulation and tissue remodeling

Aspergillus fumigatus is the etiologic agent of invasive aspergillosis, a life-threatening fungal pneumonia initiated by the inhalation of conidia into the lung. If the conidia are not cleared, they secrete large quantities of hydrolytic enzymes and toxins as they grow, causing extensive pulmonary damage. Fibroblasts are central mediators of tissue repair in many organs, but their functional response to pulmonary damage caused by A. fumigatus remains unexplored. Here, we employ cell lineage tracing, targeted cell ablation, and single-cell RNA sequencing to monitor fibroblast dynamics upon exposure to A. fumigatus in immunocompetent and immunosuppressed hosts. We find that a subset of pulmonary fibroblasts becomes activated in an immunocompetent host following a challenge with A. fumigatus conidia, initiating a gene expression program with acquired immunomodulatory properties and enhanced extracellular matrix-secreting capacity. Remarkably, targeted ablation of fibroblasts expressing the profibrotic activation marker periostin shows that invasive A. fumigatus infection accelerates in the absence of periostin lineage cells, accompanied by aberrant immune infiltration, tissue damage and severe alveolar hemorrhage. These findings uncover a protective immunomodulatory role for fibroblasts in limiting A. fumigatus-induced pulmonary injury and emphasize the importance of the pulmonary stroma in host defense against this invasive fungal infection.